DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc.
DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc.
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DNA 甲基化介导的 miR-449c 下调通过直接靶向癌基因 c-Myc 控制骨肉瘤细胞周期进展
DOI：
10.7150/ijbs.19476
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发表时间：
2017
影响因子：
9.2
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Li Q;Li H;Zhao X;Wang B;Zhang L;Zhang C;Zhang F
MicroRNAs(MiRNAs)是基因表达的关键调节因子，在包括癌症在内的各种疾病的发病机制中发挥着广泛的作用。在人骨肉瘤细胞中，miRNAs的研究和表达谱有限。通过应用miRNA微阵列分析，我们观察到许多在骨肉瘤患者癌组织中异常表达的miRNAs。这项研究特别感兴趣的是miR-449c，它在骨肉瘤细胞和患者中显著下调，其表达与肿瘤大小和肿瘤MSTS分期呈负相关。异位表达miR-449c显著抑制骨肉瘤细胞增殖和集落形成能力，并使细胞周期停滞于G1期。进一步分析表明miR-449c能够直接靶向癌基因c-Myc并负调控其表达。C-Myc的过表达部分逆转了miR-449c模拟抑制细胞的增殖和集落形成。此外，在骨肉瘤细胞中还观察到了miR-449c基因组位点附近的两个CpG岛上的DNA高甲基化。相反，用DNA甲基化抑制剂AZA处理会导致miR-449c的诱导。总之，我们的结果支持一个模型，即DNA甲基化介导miR-449c的下调，减弱miR-449c介导的对c-Myc的抑制，从而导致下游靶点的激活，最终促进骨肉瘤的发生。
MicroRNAs (miRNAs) are critical regulators of gene expression, and they have broad roles in the pathogenesis of different diseases including cancer. Limited studies and expression profiles of miRNAs are available in human osteosarcoma cells. By applying a miRNA microarray analysis, we observed a number of miRNAs with abnormal expression in cancerous tissues from osteosarcoma patients. Of particular interest in this study was miR-449c, which was significantly downregulated in osteosarcoma cells and patients, and its expression was negatively correlated with tumor size and tumor MSTS stages. Ectopic expression of miR-449c significantly inhibited osteosarcoma cell proliferation and colony formation ability, and caused cell cycle arrest at the G1 phase. Further analysis identified that miR-449c was able to directly target the oncogene c-Myc and negatively regulated its expression. Overexpression of c-Myc partially reversed miR-449c-mimic-inhibited cell proliferation and colony formation. Moreover, DNA hypermethylation was observed in two CpG islands adjacent to the genomic locus of miR-449c in osteosarcoma cells. Conversely, treatment with the DNA methylation inhibitor AZA caused induction of miR-449c. In conclusion, our results support a model that DNA methylation mediates downregulation of miR-449c, diminishing miR-449c mediated inhibition of c-Myc and thus leading to the activation of downstream targets, eventually contributing to osteosarcoma tumorigenesis.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
13.5
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
通讯作者：
Patel, Tushar
DOI：
10.1073/pnas.0808042106
发表时间：
2009-03-03
影响因子：
11.1
作者：
Sachdeva, Mohit;Zhu, Shoumin;Mo, Yin-Yuan
通讯作者：
Mo, Yin-Yuan
影响因子：
3.1
作者：
Han, Gang;Wang, Yan;Bi, Wenzhi
通讯作者：
Bi, Wenzhi
影响因子：
11.2
作者：
Sampson, Valerie B.;Rong, Nancy H.;Krueger, Leslie J.
通讯作者：
Krueger, Leslie J.